The primary goal of this revised proposal is to further our understanding of hypocretin/histamine interaction in the control of wakefulness and their respective involvement in the pathophysiology of human narcolepsy and other excessive daytime sleepiness (EDS) disorders, in order to improve treatment modalities in humans. As a result of recent progress in animal and human studies, it has now been demonstrated that impaired hypocretin (orexin) ligand production is a major pathophysiological mechanism for most human narcolepsy-cataplexy. However, the mechanisms of how hypocretin deficiency induces EDS and cataplexy are largely unknown. A series of experiments have suggested that the histaminergic system is one of the most important executive systems for mediating the wake-promoting effects of hypocretin. We also found that brain histaminergic levels are significantly reduced in the canine model of narcolepsy. It is therefore all but guaranteed that a better understanding of the physiological and pharmacological roles hypocretin and histamine interactions will lead to the development of better treatment options for sleep disorders in humans. In the revised proposal, we will (1) study physiological roles of the histaminergic system as one of the critical output neurotransmitter systems that mediate the effects of hypocretin on wakefulness and other physiological functions, (2) study changes in histamine levels and release in the brains of hypocretin cell- targeting hypocretin-deficient narcoleptic mice, and (3) evaluate the effects of histaminergic compounds on sleep and cataplexy using the hypocretin-ligand deficient mouse model of narcolepsy. We believe that results from these studies will bring new insights regarding the roles of the hypocretin/histamine interaction in narcolepsy and other EDS disorders and better treatment modalities in humans.